Neural circuitry underlying pain modulation: expectation, hypnosis, placebo.

The ability to predict the likelihood of an aversive event is an important adaptive capacity. Certainty and uncertainty regarding pain cause different adaptive behavior, emotional states, attentional focus, and perceptual changes. Recent functional neuroimaging studies indicate that certain and uncertain expectation are mediated by different neural pathways-the former having been associated with activity in the rostral anterior cingulate cortex and posterior cerebellum, the latter with activation changes in the ventromedial prefrontal cortex, mid-cingulate cortex and hippocampus. Expectation plays an important role not only in its modulation of acute and chronic pain, but also in other disorders which are characterized by certain expectation (specific phobias) or uncertain expectation (generalized anxiety disorder) of aversive events.

Utilizing brain imaging for analgesic drug development.

Analgesia is defined as loss of pain sensation without loss of consciousness; pain may be acute or chronic. Acute pain is well understood and can be controlled with currently available analgesics. Chronic pain, however, is not effectively controlled with current analgesics and side effect profiles often limit the use of these agents. Currently there are: (i) no objective methods for defining pain or analgesia in humans; (ii) no objective methods for correlating efficacy of analgesics in animal testing with human testing; and (iii) no objective method of evaluating the efficacy of analgesics in painful conditions, including neuropathic pain in which adaptive or maladaptive changes evolve with time. A technological revolution in functional brain imaging in humans and animals offers new approaches to objective evaluation of analgesics and of clinical pain states. These approaches hold great promise for revolutionizing drug development at preclinical and clinical stages.

Combining fMRI with a pharmacokinetic model to determine which brain areas activated by painful stimulation are specifically modulated by remifentanil.

We present a method for investigating the dynamic pharmacological modulation of pain-related brain activity, measured by BOLD-contrast fMRI. Noxious thermal stimulation was combined with a single infusion and washout of remifentanil, a short-acting opioid analgesic agent. The temporal profile of the effect site concentration of remifentanil, estimated from a pharmacokinetic model, was incorporated into a linear model of the fMRI data. The methodology was tested in nine healthy male subjects. During each imaging session the subjects received noxious thermal stimulation to the back of the left hand, prior to infusion, during infusion to a remifentanil effect site concentration of 1.0 ng/ml, and during washout of the remifentanil. Infusions were repeated with saline. Remifentanil-induced analgesia was confirmed from subjective pain intensity scores. Pain-related brain activity was identified in a matrix of regions using a linear model of the transient BOLD responses to noxious stimulation. Of those regions, there was a significant fractional reduction in the amplitude of the pain-related BOLD response in the insular cortex contralateral to the stimulus, the ipsilateral insular cortex, and the anterior cingulate cortex. Statistical parametric mapping of the component of pain-related BOLD responses that was linearly scaled by remifentanil concentration confirmed the contralateral insular cortex as the pain-processing region most significantly modulated by remifentanil compared to saline. The mapping of specific modulation of pain-related brain activity is directly relevant for understanding pharmacological analgesia. The method of examining time-dependent pharmacological modulation of specific brain activity may be generalized to other drugs that modulate brain activity other than that associated with pain.

Imaging attentional modulation of pain in the periaqueductal gray in humans.

Pain is an unpleasant sensory and emotional experience usually triggered by stimulation of peripheral nerves and often associated with actual or potential tissue damage. It is well known that pain perception for patients and normal subjects can be modulated by psychological factors, such as attention, stress, and arousal. Our understanding of how this modulation occurs at a neuroanatomical level is poor. Here we neuroanatomically defined a key area in the network of brain regions active in response to pain that is modulated by attention to the painful stimulus. High-resolution functional magnetic resonance imaging was used to define brain activation to painful heat stimulation applied to the hand of nine normal subjects within the periaqueductal gray region. Subjects were asked to either focus on or distract themselves from the painful stimuli, which were cued using colored lights. During the distraction condition, subjects rated the pain intensity as significantly lower compared with when they attended to the stimulus. Activation in the periaqueductal gray was significantly increased during the distraction condition, and the total increase in activation was predictive of changes in perceived intensity. This provides direct evidence supporting the notion that the periaqueductal gray is a site for higher cortical control of pain modulation in humans.

Imaging how attention modulates pain in humans using functional MRI.

Current clinical and experimental literature strongly supports the phenomenon of reduced pain perception whilst attention is distracted away from noxious stimuli. This study used functional MRI to elucidate the underlying neural systems and mechanisms involved. An analogue of the Stroop task, the counting Stroop, was used as a cognitive distraction task whilst subjects received intermittent painful thermal stimuli. Pain intensity scores were significantly reduced when subjects took part in the more cognitively demanding interference task of the counting Stroop than in the less demanding neutral task. When subjects were distracted during painful stimulation, brain areas associated with the affective division of the anterior cingulate cortex (ACC) and orbitofrontal regions showed increased activation. In contrast, many areas of the pain matrix (i.e. thalamus, insula, cognitive division of the ACC) displayed reduced activation, supporting the behavioural results of reduced pain perception.